1. Field of the Invention
The present invention relates generally to a method for administering protein phosphatase inhibitors to an individual to diminish myocardial infarction and minimize cell injury or death in ischemic tissue. Specifically, the present invention relates to a method for administering fostriecin, or a compound structurally related to fostriecin, to an individual to diminish myocardial infarction and delay cell injury or death in ischemic cardiac tissue following infarction. Beneficial therapeutic effects are achieved when fostriecin, or a compound structurally related to fostriecin, is administered either before or after the onset of a myocardial infarction.
2. Description of the Related Art
In Western countries, myocardial infarction is among the most common diagnoses in hospitalized patients. In the United States, approximately 1.5 million myocardial infarctions (MIs) occur each year, and mortality with acute infarction is approximately 30 percent (Pasternak, R. and Braunwald, E., Acute Myocardial Infarction, HARRISON'S PRINCIPLES OF INTERNAL MEDICINE, 13th Ed., McGraw Hill Inc., p.p. 1066-77 (1994)). More than half of the deaths that result from myocardial infarction occur before the patient reaches the hospital, and an additional 5-10% of survivors die in the first year (Pasternak, R. C. and Braunwald, E. Acute Myocardial Infarction, HARRISON'S PRINCIPLES OF INTERNAL MEDICINE, 13th Ed., McGraw Hill Inc., p.p. 1066-77 (1994)).
Myocardial infarction occurs generally with an abrupt decrease in coronary blood flow that follows a thrombotic occlusion of a coronary artery. The occluded artery often has been narrowed previously by atherosclerosis, and the risk of recurrent nonfatal myocardial infarction persists in many patients. Ultimately, the extent of myocardial damage caused by the coronary occlusion depends upon the "territory" supplied by the affected vessel, the degree of occlusion of the vessel, the amount of blood supplied by collateral vessels to the affected tissue, and the demand for oxygen of the myocardium whose blood supply has suddenly been limited (Pasternak, R. and Braunwald, E. Acute Myocardial Infarction, HARRISON'S PRINCIPLES OF INTERNAL MEDICINE, 13th Ed., McGraw Hill Inc., p.p. 1066-77 (1994)).
Because acute myocardial infarction frequently results in death, scientists and physicians have been studying the effects of myocardial ischemia for many years. It is hoped that, through better understanding of the processes involved in myocardial infarction, methods to minimize the deleterious effects produced by an abrupt decrease in myocardial blood flow can be developed. However, since the onset of a myocardial infarction usually cannot be predicted, the ideal treatment regime would be one that is effective when administered after the onset of the infarction process. Developing treatments that limit damage to the myocardium after the initiation of the infarction process poses a tremendous challenge.
The prognosis in acute myocardial infarction is largely related to the extent of mechanical ("pump" failure of the heart) or electrical (arrhythmia) complications. Ventricular fibrillation is the most common cause of arrhythmic failure, with death frequently occurring before the patient can reach a hospital. However, pump failure is the primary cause of in-hospital death from acute myocardial infarction, and there is a strong correlation between the degree of pump failure, the extent of ischemic necrosis, and mortality (Pasternak, R. and Braunwald, E., Acute Myocardial Infarction, HARRISON'S PRINCIPLES OF INTERNAL MEDICINE, 13th Ed., McGraw Hill Inc., p.p. 1066-77 (1994)).
An important development in the care of patients that suffer from an acute myocardial infarction is the use of pharmacologic or mechanical techniques to induce early reperfusion of the ischemic myocardium. Such techniques can "salvage" the tissue before it becomes damaged irreversibly. Since most acute myocardial infarctions are caused by thrombotic occlusion, thrombolytic agents (e.g. tissue plasminogen activator, streptokinase, and an isolated plasminogen streptokinase activator complex) can often restore coronary artery flow. Blood flow also can be restored mechanically with primary percutaneous transluminal coronary angioplasty.
Percutaneous transluminal coronary angioplasty is effective in restoring perfusion in acute myocardial infarction without having to use thrombolysis, and may be slightly more effective than present pharmacologic therapy. Still, percutaneous transluminal coronary angioplasty is expensive, requires highly trained personnel, and is limited seriously by facility requirements and other logistic considerations.
The clinical success achieved with percutaneous transluminal coronary angioplasty and thrombolytic agents has instigated a search for other mechanisms to limit the extent of ischemic damage. Of particular value would be the development of pharmacologic agents that delay the onset of cell death under ischemic conditions, compounds that enhance the survival of tissues after an ischemic episode, and/or drugs that diminish cell injury associated with reestablishment of blood flow or reperfusion. Such agents, used alone, should limit infarction size; however, they may be even more useful when employed as an adjunct to thrombolytic or percutaneous transluminal coronary angioplasty therapy.
With the exception of percutaneous transluminal coronary angioplasty and thrombolytic therapy, there are few indications that procedures to reduce the size of ischemic damage can be developed. However, the study of Murry et al., Circulation 74:1124-36 (1986), demonstrated that a significant amount of the myocardium that normally infarcts following a coronary occlusion in dogs could be salvaged if the artery was subjected first to controlled, brief occlusions, and then reperfused prior to the prolonged, myocardial infarction-causing occlusion. This phenomenon, referred to as ischemic preconditioning, was subsequently reported to occur in rabbits, pigs, rats and isolated hearts (Cohen M., et al., Cardiol. Rev. 3(3):137-49 (1995)). Claims that preconditioning has beneficial effects in humans have also been made (Deutsch, et al., Circulation, 82:2044-51 (1990); and Yellon, et al., Lancet, 342:276-77 (1993)), resulting in investigations to determine the biochemical mechanism(s) by which preconditioning leads to protection.
A possible mechanism underlying the basis for preconditioning came from studying the events that followed the onset of ischemia. Such studies revealed that many agents are released by the myocardium during ischemia, including adenosine, catecholamines, angiotensin II, bradykinin and endothelin (Cohen, et al., Ann. Rev. Med. 47:21-29 (1996)). Initial studies focused on adenosine, and it was found that drugs that block cell surface adenosine receptors completely nullified protection (see Cohen, et al., Ann. Rev. Med. 47:21-29 (1996); and Liu, et al., Circulation, 84:350-56 (1991)). This suggested protection may be receptor-mediated. Further, infusion of adenosine A.sub.1 -selective analogues in lieu of preconditioning ischemia protected the heart (Liu, et al., Circulation, 84:350-56 (1991)). Therefore, A.sub.1 -receptors were suspected as being the trigger for the protection provided by ischemic preconditioning.
Like adenosine, endogenous release of bradykinin during ischemia, or intravenous infusion of this agent, successfully preconditions rabbit myocardium, and a B.sub.2 -receptor antagonist blocks this effect. Inhibitors of other protein kinase C-coupled receptors, as well as antagonists of protein kinase C itself, also abort protection from ischemic preconditioning; and protein kinase C activators can substitute for brief ischemia and salvage ischemic myocardium in some model systems ( Cohen, et al., Cardiol. Rev. 3(3):137-49 (1995); and Cohen, et al., Ann. Rev. Med. 47:21-29 (1996)). Thus, preconditioning may arise from a series of events and the coordination of action of many interconnected pathways; or, alternatively, preconditioning may be triggered by different signal transduction pathways that act in a parallel manner.
Although studies on ischemic preconditioning have produced a better understanding of the biochemical mechanisms underlying the phenomenon, to date none of the insight has led to the production of clinically useful agents for the treatment of myocardial infarction. First, all of the aforementioned compounds have the requirement of pretreatment (treatment before the myocardial infarction episode), and there are very few situations where a physician can anticipate an impending coronary occlusion, though such a procedure may be useful where a myocardial infarction occurs to a patient during an operation. Second, it has been found that chronic treatment with an A.sub.1 -selective agonist produced tolerance within 3 days, because of either a down-regulation or decreased sensitivity of the adenosine receptor itself (Cohen, et al., Cardiol. Rev. 3(3):137-49 (1995); and Tsuchida, et. al., J. Mol. Cell Cardiol. 26:303-311 (1994)).
The prior art is deficient in the identification of pharmacological agents that can diminish myocardial infarction and delay cell injury or death in ischemic cardiac tissue after the onset of myocardial infarction. The present invention fulfills this long-standing need and desire in the art.